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Centrosomal protein72 rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

ABSTRACT: Aim:We examined the utility of the rs924607 TT genotype of the centrosomal protein 72 (CEP72) as a potential biomarker for predilection toward vincristine-induced peripheral neuropathy in children treated for acute lymphoblastic leukemia. Materials & methods:We conducted a random-effects meta-analysis of data from four studies comprising 817 patients. We tested for an association using a recessive model where a one-sided p-value < 0.05 was considered statistically significant. Results & conclusion:We were unable to confirm the association between the rs924607 TT genotype and neurotoxicity (odds ratio: 1.99; p = 0.16; 95% CI: 0.76-5.25) in our global meta-analysis. Analysis of the continuation phase (following induction) studies showed significantly higher odds for neuropathy in CEP72 rs924607 TT homozygotes (odds ratio: 2.28; p = 0.02; 95% CI: 1.16-6.87).

SUBMITTER: Zeckanovic A

PROVIDER: S-EPMC7421539 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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<i>Centrosomal protein72</i> rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

Zečkanović Aida A Jazbec Janez J Kavčič Marko M

Future science OA 20200527 7

<h4>Aim</h4>We examined the utility of the rs924607 TT genotype of the <i>centrosomal protein 72</i> (<i>CEP72</i>) as a potential biomarker for predilection toward vincristine-induced peripheral neuropathy in children treated for acute lymphoblastic leukemia.<h4>Materials & methods</h4>We conducted a random-effects meta-analysis of data from four studies comprising 817 patients. We tested for an association using a recessive model where a one-sided p-value < 0.05 was considered statistically si ...[more]

PMID: 32802391

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Project description:Simple Summary Vincristine is a type of chemotherapy that is often used in the treatment of children with cancer. The main side effect of vincristine is nerve damage. Patients experience symptoms such as tingling, pain or muscle weakness. Some children are more sensitive to vincristine than others, which may depend on variations in genes and in the breakdown of vincristine by the body. In this study, we investigated the effect of variations in genes on nerve damage due to vincristine and breakdown of vincristine by the body. We found that nine variations in seven genes were associated with nerve damage due to vincristine, whereas three variations in three genes were associated with the breakdown of vincristine by the body. It is important that future studies try to replicate these findings. Our findings help us towards the goal of tailoring vincristine treatment to each child, with optimal therapeutic effect while limiting nerve damage. Abstract Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment.

Project description:: Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adults with second or greater relapse and clinically advanced Philadelphia chromosome-negative ALL. For the first time, studies will be able to exploit the delivery of higher and uncapped doses of vincristine in randomized studies comparing first-line chemotherapy with standard vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional vincristine.This review summarizes the development of vincristine sulfate liposome injection, a new formulation of vincristine. The pharmacokinetics of liposomal drug delivery are examined, the limitations and advantages of conventional and liposomal vincristine are compared, and the use of vincristine sulfate liposome injection in clinical trials and case studies is included. Clinicians will be informed of a new chemotherapy agent that is indicated for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia, whose disease has relapsed two or more times or whose leukemia has progressed after two or more regimens of antileukemia therapy.

Project description:ImportanceWith cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment.ObjectiveTo identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL.Design, setting, and participantsGenome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity.ExposureTreatment with vincristine at a dose of 1.5 or 2.0 mg/m2.Main outcomes and measuresVincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4).ResultsGrade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10(-9)). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.Conclusions and relevanceIn this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.

Dataset Information

Centrosomal protein72 rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

Publications

<i>Centrosomal protein72</i> rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

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